In the c-myc/TGF-a transgenic mouse model, hepatocellular adenoma (HCA) appear in the liver by 4 months of age and progresses to hepatocellular carcinoma (HCC) by 8-10 months of age. Histologically, a small nest of HCC are frequently observed in HCA nodules, suggesting that HCA is a pre-malignant lesion in this model. In this study we have used cDNA microarray to analyze the difference between histologically well-defined HCA and HCC tumors in molecular level. Gene expression profile analysis revealed distinctive gene expression patterns between HCA and HCC. Interestingly, gene expression pattern of one HCA tumor was similar to HCC tumors, and two HCC tumors similar to HCA tumors. Among several genes selected as potential predictors for distinguishing HCC from HCA tumors, expression of three genes (Car3, Afp, and Igfbp1) in tumors were re-examined by RT-PCR. RT-PCR results were consistent with the observation in cDNA microarray studies. Enhanced expression of angiogenin family in HCC is consistent with higher angiogenic status in HCC measured by CD31 immunostaining of tumors. Our study demonstrates that the application of unbiased analytical approaches to the gene expression profiles of mouse tumors provide us better prediction when distinguishing HCC from HCA. A set of predictor genes for the classification of tumors during development of HCC in this model was identified based on gene expression profiles of HCA and HCC. In addition, angiogenesis triggered by expression of antiogenin family appears to be the most critical event during conversion of HCA to HCC.